At least seven different receptor classes mediate the physiological activities which are attributed to an involvement of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT for short). They are designated according to an internationally recognized classification as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 snd 5-HT7. The majority of these classes additionally include further distinguishable receptor sub-types. For example, receptors belonging to the 5-HT1 class can be further subdivided in at least five sub-classes and are termed 5-HT1A, 5-HT1B, 5-HT1C5-HT1D and 5-HT1E (Boess, Martin; Neuropharmacology 33:275-317 (1994).
The 5-HT5-class was first described by Plassat et al., The EMBO Journal Bd. 11 Nr. 13, S. 4779-4786 (1992). One distinguishes between 5-HT5A and 5-HT5B receptors (Erlander et al., Proc. Natl. Acad. Sci. USA 90:3452-3456 (1993). There exists only minimal sequence homology between 5-HT5 and other 5-HT receptors, and the pharmacological profile of these receptors is markedly different. 5-HT5 receptors can be localized with the help of molecular biological techniques in the olfactory bulb, in the hippocampus, in the cortex, in the cerebal ventricles, in the corpus callosum and in the cerebellum. It was shown by immunohistochemical methods that 5-HT5 receptors are expressed in different regions of the brain (Oliver et al. Brain Res 2000, 867, 131-142; Pasqualetti et al. Mol Brain Res 1998, 56, 1-8)). These 5-HT5 receptors can on the one hand modulate functions of the brain directly or indirectly, but on the other hand they may also participate in mechanisms involved in neuropathological, neurodegenerative and neuropsychiatric diseases. 5-HT5 receptors were also localized in astrocytes (Carson et al., GLIA 17:317-326 (1996). Astrocytes lie directly on the basal membrane of brain capillaries of the blood brain barrier and an abnormal astrocyte-endothelium-structure is associated with a loss of the blood brain barrier. The exact significance of astrocytes is unclear, but they seem to assume transport roles and connective functions. Reactive astrocytes were observed in connection with reactive gliosis in a series of pathological brain changes and neuropsychiatric diseases. These astrocytes modify their morphology as a result of brain injuries. The protein expression pattern changes and growth factors are produced. In-vitro studies on cultivated astrocytes showed 5-HT5 receptor mediated responses. For this reason, it is on the one hand assumed that the 5-HT5 receptor plays a role in recovery processes of the brain after disorders; on the other hand, it cannot be excluded that they contribute to the development of damage or even to an augmentation of damage.
Diseases of the CNS currently affect large sections of the population. The numbers of patients are continually rising, especially due to the increase of older people. Neuropathological conditions such as cerebral ischemia, stroke, epilepsy and seizures in general, chronic schizophrenia, other psychotic diseases, depression, states of anxiety, bipolar disorders, dementia, in particular Alzheimer dementia, demyelinizing diseases, in particular multiple sclerosis, and brain tumors, lead to damage of the brain and to the neuronal deficits associated therewith. Up to now, therapeutic treatments of the neurodegenerative and neuropsychiatric disorders described have been directed to different membrane receptors with the goal of compensating deficits in neurotransmission processes. Neuroprotective effects with different serotoninergic compounds have been achieved in animal models for neuropathological conditions such as ischemia, stroke and excitotoxicity; in some cases beneficial effects on mood disorders, such as depression or states of anxiety, could be observed. For example 5-HT1A agonists such as buspiron, or the compound 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), characterized as a selective 5-HT1A receptor-ligand, are noteworthy in this regard. However, these agents alleviate the neurological deficits described only under certain conditions; an effective therapy for these diseases does not yet exist at the present time.
A further neuropathological disease effecting large segments of the population, is migraine. In most cases, migraine manifests itself in recurring headaches, affecting an estimated 8 million people, i.e. 3-5% of all children, 7% of all men and 14% of all women. Although a genetic predisposition is propagated, the causes seem to be complex. (Diener H. C. et al., Arzneimitteltherapie 15:387-394 (1997). Two hypotheses dominate. The vessel theory, known for a long time, suggests a dilation process of the inner and outer cerebral vessel system as a cause. The neurogenic theory is based on a release of vasoactive neurotransmitters, primarily neuropeptides, such as substance P and neurokinin from axons of the vasculature, as a result of a stimulation of certain ganglia which innervate brain tissue, which supposedly leads to inflammatory reactions and thus to pain.
A causal therapy for the treatment of migraines does not yet exist at the present time. Two different treatment methods are currently employed: a first, prophylactic therapy for the prevention of recurring migraine attacks and a second, symptomatic therapy for suppressing acute symptoms during attacks. Migraine-specific agents such as Sanmigran®, Nocerton®, Desernil® and Vidora®, as well as other agents typically used for other indications, such as beta-blockers, anti-emetic agents such as Sibelium®, anti-depressives such as Laroxyi®, or anti-epileptic agents such as Depakin®, are prophylactically administered. In the context of acute therapy, one gives analgesics, such as Aspirin®, Paracetamol® or Optalidon®, non-steroidal anti-inflammatory agents, such as Cebutid®, Voltaren®, Brufen®, Ponstyl®, Profenid®, Apranx® and Naprosin® against the pain and inflammation, ergotalkaloids, such as ergotamine, dihydroergotamine, which can trigger a vasoconstriction, or substances of the triptan-family, such as sumatriptan, Naramig®, and AscoTop® with high affinity for 5-HT1 D receptors. The latter substances function as agonists and block vasodilation.
The agents described are however not optimally suited for the treatment of migraines. Non-opioide analgesics often have side effects. The complex mode of action of ergotalkaloids leads to side effects such as hypertonia and gangrene due to the strong peripherla vasoconstriction. Compounds belonging to the triptan-family also are not completely satisfactory in their function. (Pfaffenrath V. Munch. Med. Wschr. 625-626 (1998).
The use of 5-HT5 receptor ligands in general for the treatment of migraines and other cerebralvascular diseases, is described in WO 00/041472, and in WO 00/041696 for the treatment of neurodegenerative and neuropsychiatric diseases.
Guanidine compounds have not been used as 5-HT5 ligands up to now.
Substituted guanidines are generally known as H2-antagonists, as inhibitors of the H+K+-ATPase, inhibitors of the secretion of stomach acid, and in these capacities as a means for treating PUD-syndrome (Peptic Ulcer Disease). The most diversely substituted thiazole-guanidines are generally described in the literature as compounds with anti-viral, bactericidal, anti-microbial and/or anti-inflammatory affect, as protease-inhibitors or vitronectin-antagonists.
WO-9911637 describes generally substituted N-{4-[anilinoalkyl)phenyl]-1,3-thiazole-2-yl}-benzylguanidine and their use as protease-inhibitors. WO-9850373 describes N-substituted N-[4-(phenoxyphenyl)-1,3-thiazole-2-yl]guanidine and their use as bactericides. In WO-9605187 and EP-545376 the preparation of substituted 4-(3-aminomethylphenyl)-2-thiazolylguanidines and their use as H2 receptor antagonists is described. JP-59225172 generally describes N-alkyl-substituted 4-phenylthiazolguanidines as H1 and H2 receptor antagonists and their use as inhibitors of stomach acid secretion. NL-7700083, U.S. Pat. No. 4,089,965, DE-2700951, BE-850148 describe N-aryl-substituted 4-phenyl-thiazolguanidines with anti-viral properties, especially as anti-rhinovirus agents. EP-3640 generally describes substituted N-[4-(3-aminophenyl)-1,3-thiazole-2-yl]guanidines and their anitsecretory properties. JP-0817614 describes the preparation of 2-[(diaminomethylene)amino]-4-pyrimidinylthiazolguanidines with H2-antagonistic, anti-ulcer and anti-bacterial properties.
WO-9518126, JP-09040671, WO-9403450, WO-9303028, EP-355612, U.S. Pat. No. 4,814,341 describe N-substituted 4-furylthiazolguanidines with anti-bacterial properties (in particular Heliobacter pylori) and their use for the treatment of gastritis and general PUD syndrome (ulcer, Zollinger-Ellison syndrome, oseophagititis, gastrointestinal bleeding). WO-9429304 and JP-08245621 describe corresponding 4-thienylthiazolguanidines with similar applications. WO-9216526, EP-417751 generally describe the preparation of N-substituted 4-hetaryl-substituted thiazolguanidines, especially corresponding pyridyl- and thiazolyl-derivatives, H2-antagonistic properties and their use as anti-ulcer- and anti-microbial agents. EP-259085 also describes the preparation of 4-hetaryl-substituted thiazolguanidines, especially corresponding pyrrolyl- and indolyl-derivatives for the treatment of PUD syndrome. JP-59225186 and JP-59036674 describe 4-hetaryl-substituted thiazolguanidines, especially 2-furyl- and 2-pyridyl-derivatives, and their anti-secretory properties.
WO-9324485, JP-07188197 describe 4-phenyloxazolguanidines as H2 receptor antagonists with additional anti-bacterial properties for the treatment of gastrointestinal diseases.
In the Journal of Chemical and Engineering Data 1978, 23 (2), 177-8, N-aryl-N′-2-(thiazolyl-, napthothiazolyl-, benzothiazolyl)guanidines are described as substances with anti-malaria-effect and/or analgesic properties. In Bioorg. Med. Chem. Lett. 2000 (10), 265-268, N-[2-(2-methoxyphenyl)ethyl]-N′-1,3-thiazole-2-ylguanidine is described in the context of bioisosteric modifications of PETT-HIV-1 RT-inhibitors, but the compound did not show any demonstrable biological activity. Differently substituted thiazolguanidines are described in the following literature citations as anti-microbial substances with activity against Heliobacter pyloris: 2-(substituted guanidino)-4-arylthiazole and Aryloxazole in J. Med. Chem. 2002, 45(1), 143-150; 2-(substituted guanidino)-4-phenylthiazole and rigidized derivatives in J. Med. Chem. 2000, 17, 3315-3321; 2-[(arylalkyl)guanidino]-4-furylthiazole in J. Med. Chem. 1999, 42(15), 2920-2926; alkylguanidino-4-furylthiazole in Bioorg. Med. Chem. Lett. 1998, 8(11), 1307-1312; 2-(alkylguanidino)-4-furylthiazole and analogs in J. Med. Chem. 1997, 40(16), 2462-2465. 4-substituted 2-guanidinothiazoles and 4-indolyl-2-guanidinothiazoles are described as inhibitors of the H+, K+-ATPase in J. Med. Chem. 1990, 33, 543-552; and THEOCHEM 2001, 539, 245-251; THEOCHEM 2002, 580, 263-270, respectively.